Sodium dimandelic acid ether (SAMMA) is a non-cytotoxic, contraceptive antimicrobial agent that appears to function by inhibiting sperm and viral function. The compound does not contain sulfur which differentiates it from most other non-cytotoxic "entry inhibitors" developed so far. SAMMA prevents fertilization in the rabbit when mixed with spermatozoa or placed vaginally as a gel before insemination; The compound also causes the dispersion of the acrosome from human spermatozoa. Physiologically, such dispersion (acrosome reaction) occurs when the spermatozoon approximates the oocyte, enabling sperm binding to and penetration of the layers surrounding the egg. Premature acrosomal loss, i.e., in the vagina, should render spermatozoa incapable of fertilizing. Therefore, the acrosomal loss-inducing capacity of SAMMA may be the primary reason for its contraceptive properties. Acrosomal loss of both capacitated and non-capacitated spermatozoa caused by modulators is usually calcium ion dependent and is mediated by signal transduction cascades involving one or more protein kinases; candidates include phospholipid-dependent kinase (PKC), CAMP-dependent kinase (PKA), cGMP-dependent kinase (PKG) and protein tyrosine kinase (PTK). The first two objectives of the Project are to determine whether the induction of acrosomal loss by SAMMA is mediated by an effect on calcium transport and/or on one or more of the protein kinases (Aims 1 and 2). The third objective is to assess the structural requirements for SAMMA and its derivatives to induce acrosomal loss through these mechanisms (Aim 3). The final objective is to obtain and test highly active SAMMA derivatives, based on these structural requirements, and to select the most effective SAMMA derivatives based on their ability to induce acrosomal loss and their potency in the rabbit contraceptive assay (Aim 4). The isomers of the active SAMMA derivative will also be compared for their relative activity in the acrosomal loss assay and in the contraceptive test (Aim 4). As a result of these studies, the mechanism of SAMMA's acrosomal loss-inducing activity will be better understood, and can be compared to its mechanism of antiviral action (evaluated in the other projects). If similar, this would help explain the ability of SAMMA to be both antimicrobial and contraceptive, and can lead to the development of other non-cytotoxic entry inhibitors with dual activity. In addition, the most active SAMMA derivative/isomer will have been selected and can be developed further through the pre-IND stages into clinical trial.